The ability to reliably detect and track individual neurons with sufficient temporal resolution in time scale commensurate with learning and memory is critical to both basic and translational neurosciences. Chronically implanted neural electrodes constitute the only means to electrically interact with living brains at sub- millisecond time scale and single neuron resolution, but suffer from persistent interface degradation that leads to substantial recording condition changes in both the short and long term. There is a growing awareness that addressing the dimension and mechanical properties of the neural probe might improve the interface. However, neural probes that provide reliable recording for extended periods with no chronic detrimental effects pose stringent requirement on the robustness and bio-compatibility of the device, which are yet to be developed. The overall objective of this project is to achieve stable tissue-probe interface and reliable electrical recording by developing, testing and optimizing nanoelectronic thread (NET) neural probes. This will be studied by extensive in vitro characterization and in vivo in rodent models (mouse and rat) where the tissue-probe interface and the neural probe recording conditions will be monitored and evaluated over chronical implantation durations. Repeated in vivo imaging of the cellular and vascular evolution near the implanted probes will be used together with postmortem histology studies and comprehensive characterization of the chronical recording performance to assess and optimize the functionality of NET probes. The central hypothesis of the project, on the basis of strong preliminary data from the applicant's laboratory, is that chronically reliable electrical recording with non-degrading tissue-probe interface can be achieved by matching the neural probe physical properties, in particular the dimensions, the surgical footprint and the mechanical flexibility, with that of the cellular networks in living brain. The specific aims are to test this hypothesis: 1) Design and optimize NET probes for long-term in-vivo structural stability; 2) Evaluate and optimize the long-term biocompatibility of the NET probes; and 3) Verify and optimize long-term reliable recording and tracking of individual neurons. The approach is innovative, in the applicants' opinion, because it represents a new and substantive departure from the status quo by focusing on the aggressive reduction of the dimension and rigidity of the neural recording devices into previously unattainable regimes. The long-term goal of this project is to identify key design parameters that enable chronically stable integration between man-made devices and living brain tissue so that these parameters can be applied to guide the design of a variety of neural implants for advancing fundamental neuroscience and benefitting neurological condition treatments. The unprecedented chronic reliability and stability in electrical recording expected to be achieved in this project will also lead to substantial improvement in the brain-machine interface that can be applied to neuroprosthetics.